• Major finding: Oligodendrocyte precursor cells identified as glioma cell of origin.

  • Method: MADM used to follow entire tumorigenic process.

  • Significance: Cell of mutation and cell of origin can differ.

A cancer “cell of origin” is a specific cell type that can progress to a tumor due to a permissive signaling context that results from a set of particular genetic abnormalities. Better understanding of cell of origin should help determine tumor origin, identify mechanisms of tumorigenesis, predict tumor biology and behavior, and develop strategies for rational intervention. However, the cell of origin can be difficult to identify based on the heterogeneous cell population in late-stage patient tumors. Therefore, researchers have increasingly turned to mouse models to identify cell of origin. Now, Liu and colleagues have used mosaic analysis with double markers (MADM) to identify the cell of origin in a mouse model of glioma. The authors genetically inactivated p53 and NF1 in neural stem cells (NSC) labeled with green fluorescent protein and followed all NSC-derived lineages. They determined that oligodendrocyte precursor cells (OPC) were overrepresented in a “pretransforming” stage and maintained their proliferative capacity. Gliomas that eventually arose in these mice expressed OPC markers. Very interestingly, NSCs containing mutant p53 and NF1 did not show overexpansion, suggesting that the cell of mutation and cell of origin can differ. To confirm the ability of OPCs to transform, p53 and NF1 were inactivated only in this cell type, and mice developed tumors. These findings highlight the utility of MADM in following the entire tumorigenic process and precisely identifying cell of origin. Such knowledge should help in the design of effective drugs that target the vulnerability of signaling pathways in the cell of origin that are perturbed by particular genetic mutations.

Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 2011;146:209–21.

Note:Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.